PARP is short for “poly (ADP-ribose) polymerase”. Cancer cells use the enzyme PARP to repair DNA damage, including the damage inflicted by chemotherapy drugs. Researchers are examining whether drugs that inhibit the enzyme PARP will diminish this self-repair mechanism and make cancer cells more sensitive to the treatment and promotion of cancer cell death.
PARP inhibitors are a group of pharmacological inhibitors of the enzyme Poly ADP ribose polymerase (PARP), which is important for facilitating DNA repair, controlling RNA transcription, mediating cell death and regulating immune response. Therefore, the PARP inhibitors are developed for multiple indications; the most important indication is cancer. Several types of cancer are more dependent on PARP than regular cells, making PARP an attractive target for chemotherapeutic cancer therapy.
There is considerable interest in the development of PARP inhibitors as chemo sensitizers for use in cancer therapy and to limit cellular damage after ischemia or endotoxic stress. Cytotoxic drugs, generally, or radiation can induce activation of PARP, and it has been demonstrated that inhibitors of PARP can potentiate the DNA damaging and cytotoxic effects of chemotherapy and irradiation (see Kock, et al, 45, J. Med. Chem. 4961, 2002). PARP mediated DNA repair in response to DNA damaging agents represents a mechanism for drug resistance in tumors, and the inhibition of this enzyme has been shown to enhance the activity of ionizing radiation and several cytotoxic antitumor agents, including temozolomide and topotecan. Suto et al, in U.S. Pat. No. 5,177,075, disclosed several isoquino lines used for enhancing the lethal effects of ionizing radiation or chemotherapeutic agents on tumor cells. Weltin et al, “Effect of 6(5H)-Phenanthridinone, an Inhibitor of Poly (ADP-ribose) Polymerase, on Cultured Tumor Cells”, Oncol. Res., 6:9, 399-403 (1994) disclosed that the inhibition of PARP activity reduced proliferation of tumor cells, and produced a marked synergistic effect when tumor cells are co-treated with an alkylating drug. PARP is thus a potentially important therapeutic target for enhancing DNA-damaging cancer therapies.
PARP inhibitors can also inhibit the growth of cells having defects in the homologous recombination (HR) pathway of double-stranded DNA repair, see, for example, Bryant et al, “Specific killing of BRCA2-deficient tumors with inhibitors of poly (ADP-ribose) polymerase,” Nature 434, 913 (2005); Farmer et al, “Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy,” Nature 434, 917 (2005). This effect operates without the presence of chemosensitizers. Known states associated with HR defects include BRCA-1 defects, BRCA-2 defects, and Fanconi anemia-associated cancers (McCabe et al., “Deficiency in the Repair of DNA Damage by Homologous Recombination and Sensitivity to Poly (ADP-Ribose) Polymerase Inhibition,” Cancer Res. 66. 8109, 2006). Proteins identified as associated with Fanconi anemia include FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCL, and FANCM. Id. For reviews, see Zaremba et al., “PARP Inhibitor Development for Systemic Cancer Targeting,” Anti-Cancer Agents in Medicinal Chemistry 7, 515 (2007), and Lewis et al., “Clinical poly(ADP-ribose) polymerase inhibitors for the treatment of cancer,” Curr. Opin. Investigational Drugs 8, 1061 (2007).
Large numbers of known PARP inhibitors have been described in Banasik et al., “Specific Inhibitors of Poly (ADP-Ribose) Synthetase and Mono (ADP-Ribose)-Transferase”, J. Biol. Chem., 267:3, 1569-75 (1992), and in Banasik et al., “Inhibitors and Activators of ADP-Ribosylation Reactions”, Molec. Cell. Biochem., 138, 185-97 (1994).
In addition to the above, PARP inhibitors have been disclosed and described in the following international patent applications: WO09/04356, WO04/80976, WO 00/42040; WO00/39070; WO00/39104; WO99/11623; WO99/11628; WO99/11622; WO 99/59975; WO99/11644; WO99/11945; WO99/11649; and WO99/59973. PARP-inhibitors that potentiate the lethality of cytotoxic agents by chemosensitizing tumor cells to the cytotoxic effects of chemotherapeutic agents has been reported in, inter alia, US2002/0028815; US2003/0134843; US2004/0067949; White A W, et al., 14 Bioorg. and Med. Chem. Letts. 2433 (2004); Canon Koch S S, et al., 45 J. Med. Chem. 4961 (2002); Skalitsky D J, et al, 46 J. Med. Chem. 210 (2003); Farmer H, et al, 434 Nature 917 (14 Apr. 2005); Plummer E R, et al., 11(9) Clin. Cancer Res. 3 402 (2005); Tikhe J G, et al., 47 J. Med. Chem. 5467 (2004); Griffin R. J., et al, WO98/33802; and Helleday T, et al, WO2005/012305.
In addition to cancer therapy, PARP inhibitors are considered as a potential drug for acute, life-threatening diseases, such as stroke and myocardial infarction, diabetes, inflammation, as well as a long-term drug for neurodegenerative diseases (Graziani G, Szabó C (July 2005). “Clinical perspectives of PARP inhibitors”. Pharmacol. Res. 52 (1): 109-18).